Erythema is a skin condition characterized by redness of the skin. It occurs with skin injury, infection, or inflammation. It can also occur as a reaction to medications, illness or emotions. The causes for some erythema are presently unknown. Currently available treatments for erythema are of limited effectiveness.
Topical alpha-adrenergic agonists are used to treat erythema, typically of the face. Topical brimonidine tartrate, a selective alpha2-adrenergic agonist, is FDA and EMA-approved to treat facial erythema secondary to rosacea under the names Mirvaso® and Onreltea. U.S. Patent Publication Nos. 20050020600, 20160095857 and 20090061020. U.S. Pat. No. 7,439,241. Topical alpha-adrenergic agonists can be used to treat erythema caused by, e.g., rosacea, menopausal flushing, and ingestion of spicy food or alcoholic drinks. In addition, topical alpha-adrenergic agonists are being investigated to treat erythema caused by botulinum toxin (Botox), dermal filler injections, vascularized scars, intense pulsed-light (IPL) laser treatment and daylight-activated photodynamic therapy, as well as injection site erythema caused by biologic medications which are used to treat conditions such as rheumatoid arthritis, multiple sclerosis and other autoimmune diseases. Markus et al., Photo letter to the editor: Topical 0.5% brimonidine gel to camouflage redness of immature scars, J Dermatol Case Rep. 2015 Sep. 30; 9(3): 87-88. Gerber P A, Topical brimonidine tartrate 0.33% gel effectively reduces the post-treatment erythema of daylight-activated photodynamic therapy, Br J Dermatol. 2016; 174(6):1422-3. Braun et al., Brimonidine tartrate 0.33% gel for the management of posttreatment erythema induced by laser skin resurfacing, J Am Acad Dermatol. 2017; 76(2):e53-e55. Brimonidine tartrate for the treatment of injection related erythema (BRITE), Clinicaltrials.gov, Identifier NCT02568111. Reports have also indicated its effectiveness for capillary hemangiomas in children and as a hemostatic agent in dermatologic surgery. Brimonidine gel is also being investigated for reducing injection site erythema in patients receiving immunomodulatory therapy for multiple sclerosis and as agents for treating certain UV-induced cutaneous neoplasms.
A significant side effect affecting approximately 10-20% of users of topical alpha-adrenergic agonists is late-onset erythema that occurs when the effect of the drug wears off, usually occurring 8 to 24 hours following initial application. Docherty et al., Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy, Adv Ther. 2016; 33(11):1885-1895. Werner et al., Dermatitis medicamentosa: severe rebound erythema secondary to topical brimonidine in rosacea, Dermatol Online J, 2015 Jan. 1; 21(3). Tanghetti et al., Optimizing the use of topical brimonidine in rosacea management: panel recommendations, J Drugs Dermatol. 2015 January; 14(1):33-40. This late-onset erythema has also been referred to as “paradoxical erythema”, “rebound erythema” or “rebound flushing”. It has been suggested that topical alpha-adrenergic agonists cause vasoconstriction and decrease cutaneous blood flow, which in turn reduce cutaneous flushing or erythema. Without being limited to any specific physiological mechanism, it is suggested that after several hours of cutaneous vasoconstriction and limitation of blood flow, both oxygen levels and pH in the skin are reduced. These two conditions can contribute to an increase in the cutaneous levels of substance P, an undecapeptide member of the tachykinin neuropeptide family. Substance P acts to stimulate vasodilation by inducing production of nitric oxide (NO) and causing mast cell degranulation. Ebertz et al., Substance P-induced histamine release in human cutaneous mast cells, J Invest Dermatol. 1987; 88(6):682-5. Hakanson et al., Substance P antagonists release histamine from peritoneal mast cells, Acta Physiol Scand. 1983 February; 117(2):319-20. NO is a potent vasodilator whereas degranulation of mast cells releases histamine, another potent vasodilator.
Capsaicin is the main capsaicinoid in capsicum plants including chili peppers. Cordell et al., Capsaicin: identification, nomenclature, and pharmacotherapy. Annals of Pharmacotherapy. 1993: 27:330-336. Capsaicin is known to induce vasodilation and protein extravasation caused by the release of substance P, from axons of unmyelinated C-fibers of sensory nerves. Carpenter et al., Vascular and sensory responses of human skin to mild injury after topical treatment of capsaicin, Br. J. Pharmacol., 1981, 73:755-758. Fitzgerald, Capsaicin and sensory neurons—a review, Pain, 1983, 15: 109-130.
Capsaicin is used clinically as an analgesic in topical ointments, nasal sprays and dermal patches. It is currently marketed for topical administration to treat pain in conditions such as peripheral neuropathy, post-herpetic neuralgia, diabetic neuropathy, osteoarthritis, shingles (herpes zoster), psoriasis, and HIV neuralgia. Martin Hautkappe et al., Review of the Effectiveness of Capsaicin for Painful Cutaneous Disorders and Neural Dysfunction, Clin. J. Pain, 14:97-106, 1998. Capsaicin is also available over the counter to treat minor muscle aches, arthritis and sprains. Topical capsaicin has been found to be safe and effective with little to no systemic absorption.
Capsaicin can elicit erythema and/or an intense burning or stinging sensation upon topical application. Watson et al., A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia, Clinical Therapeutics. 15.3 (1993):510-526. Peikert, A. et al., Topical 0.025% capsaicin in chronic post-herpetic neuralgia: efficacy, predictors of response and long-term course, J. Neural. 238:452-456, 1991; Watanabe, A. et al, Efficacy of capsaicin ointment (Zostrix) in the treatment of herpetic pain and postherpetic neuralgia, Pain Clinic 15:709-713, 1994.
There is a need to reduce late-onset cutaneous erythema associated with the use of topical alpha adrenergic agonists.